Histone acetylation, increase leads to Altered, Gene Expression

In all eukaryotes, the DNA containing the genetic information of an organism is organized in chromatin. The basic unit of chromatin is the nucleosome around which the naked DNA is wrapped. A nucleosome consists of two copies of each of the core histones H2A, H2B, H3 and H4 (Luger et al., 1997). In general, chromatin is a permissive structure for all DNA-dependent processes such as DNA replication, recombination, repair, and transcription and therefore also for gene expression. However, chromatin structure is very dynamically regulated and can be made accessible for the transcriptional machinery and is, therefore, an important mechanism of gene regulation. One mechanism of chromatin structural regulation is the post-translational modifications of the histone proteins including the acetylation of lysine residues (reviewed in (Bannister and Kouzarides, 2011; Bannister et al., 2002; Kouzarides, 2007; Tessarz and Kouzarides, 2014)). These modifications serve as a docking station for further proteins and protein complexes that finally open or close the chromatin structure and allow or inhibit access of the transcriptional machinery (Musselman et al., 2012) or directly influence DNA histone interaction (reviewed in (Tessarz and Kouzarides, 2014). Histones get acetylated by histone acetyltransferases (HAT) and deacetylated by histone deacetylases (HDAC) (reviewed in (Gallinari et al., 2007; Bannister and Kouzarides, 2011; Kouzarides, 2007)). In general, it can be assumed, hyperacetylated histones are associated with actively transcribed genes, whereas hypoacetylation of histones is involved in gene silencing.

The first direct evidence that histone acetylation has an impact on gene expression came from mutation studies in yeast. Using ChIP on chip analysis showed that mutation or deletions of HDAC enzymes lead to changed gene expression levels on a subset of genes (Xu et al., 2005; Bernstein et al., 2000; Robyr et al., 2002).

In the Drosophila cell line S2, it was shown that deregulation of transcription occurs only by know-down (RNAi) HDAC enzymes, that at least class 1 and 3 HDAC enzymes have an influence on gene expression (measured via gene chips). However, this study did not show a direct link between histone acetylation and gene expression (Foglietti et al., 2006).

In mice knockout of HDACs are mostly embryonically lethal. However, the use of embryonic stem cells and the expression and acetylation profiles shows that also in mice an imbalance of histone acetylation may lead to changes in gene expression (Zupkovitz et al., 2006).

Major gene expression changes were observed during the differentiation of hESC towards neuroectodermal progenitor cells. In these studies also the acetylation status of the deregulated genes was investigated by chromatin immunoprecipitation (Balmer et al., 2014; Balmer et al., 2012)

All above-mentioned analysis are indirect or in purified systems. Therefore a direct cause-consequence relation is difficult to obtain.